tbuckley/cabot-search huggingface dataset:
ATRT-19. RARE EMBRYONAL TUMORS INCLUDING EMBRYONAL TUMOR MULTILAYER ROSETTE, OUTCOME AND PATTERN OF TREATMENT FAILURE: MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Jiasen He, Faryal Munir, Irtiza Sheikh, Jason Johnson, Arnold Paulino, Susan McGovern, David Sandberg, Wafik Zaky
Journal: Neuro-Oncology (2023)

Abstract Rare embryonal tumors (excluding medulloblastoma and ATRT) are aggressive pediatric cancers that include embryonal tumor with multilayer rosettes (ETMR), embryonal tumor with abundant neuropil and true rosettes (ETANTR), and embryonal tumors not otherwise specified (ET-NOS). The presence of driver events like C19MC amplification, DICER1 mutations and other microRNA-related aberrations are vital in diagnostic classification of these tumors. The prognosis of these tumors is dismal despite intensive multimodal treatments with the 5-year overall survival being less than 30%. We retrospectively reviewed 12 patients with rare embryonal tumors who were treated at MD Anderson Cancer Center from 2010 to 2022. Of the 12 patients identified, the mean age at diagnosis was 3.6 years (range: 1-12 years) with no sex differences. Histologically, they were classified into ETMR (4/12), ETANTR (3/12) and ET-NOS (5/12) with C19MC found positive in 2/4 ETMR cases. All patients presented with large infiltrative tumors to the supratentorial (6/12), brainstem (4/12), and spinal (2/12) regions. The majority of patients (10/12) were treated by gross/subtotal resection. Treatment at diagnosis included surgery alone (3/12), surgery with chemotherapy (4/12), surgery with chemotherapy plus radiation (4/12),and chemotherapy plus radiation without surgery (1/12). Five patients reported with de-novo metastasis and 10/12 patients had disease progression at 4.1 months of median follow-up (range: 1.2-10.6 months). Six patients had local recurrence and three patients had local with distant disease at progression. Eight patients are still alive, with 5/8 of them surviving more than 5 years. In conclusion, these rare embryonal tumors are hard to diagnose and treat effectively. Even with successful surgery and intense chemotherapy, almost all of them progress/relapse but combined treatments seem to be effective in a subset of patients. Collaborative multi-institutional efforts are required to define standard treatment approaches and future patient stratification.
HGG-15. HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS
Authors: Matthew Clarke, Rita Pereira, Alan Mackay, Yura Grabovska, Amelia Clarke, James Nicoll, John Procter, Andrew Moore, Joanna Schagen, Liam Walker, Federico Roncaroli, Olumide Ogunbigi, Thomas Jacques, Lynley Marshall, Fernando Carceller, Zita Reisz, Safa Al-Sarraj, Maria Vinci, Kathreena Kurian, H K Ng, Sebastian Brandner, Chris Jones
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas (HGG) arise in any central nervous system location, in adults and children, with a poor prognosis. HGGs in teenagers and young adults (TYA) are understudied; this project aimed to characterise these tumours and identify potential therapeutic targets. HGG samples (n=195, FFPE/FF, 13-30 years) were collected, excluding well-characterised entities (histone/IDH-mutant). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package), n=195) classified cases against a reference cohort. Calibrated scores guided workflows to characterise mutational landscapes including RNA-based ArcherDx fusion panel (n=112), whole exome sequencing (n=84), and histological reviews in parallel. Well-characterised entities (n=50, including IDH-mutant tumours (n=18), PXA (n=12)) were excluded. Of the cases scoring &amp;gt;0.6, 64% classified as paediatric-type subgroups (pedHGG-RTK1A/B/C (30%), pedHGG-MYCN (10%), pedHGG-A/B (7%), pedHGG-RTK2A (6%)). 29% classified as subgroups more frequently seen in adults (GBM-MES (12%), GBM-RTK1/2 (3%)). 54% classified with a score &amp;lt;0.6. 38% cases were assigned to novel, recently identified, poorly-characterised subgroups with distinct methylation profiles and molecular features (HGG-B, HGG-E, ANTCON, GBM-CBM). Frequency comparisons to publicly available methylation data showed GBM-MES-ATYP tumours are TYA age-specific, in contrast to adult age-specific GBM-MES-TYP. Copy number profiling identified frequent changes across the cohort, including chromosomal gains (chr1q (54%), chr2 (22%), chr7 (41%)) and losses (chr10 (40%), chr13 (64%)). Focal amplifications included PDGFRA (12%), CDK4 (7%), MYCN/ID2 (3%), MYC (2%) and EGFR (0.7%) and the most common focal deletion was CDKN2A/p16 (12%). The most frequent glioma-associated somatic variants included TP53, PDGFRA, EGFR, and NF1. BCOR alterations were enriched compared to adult and paediatric reference cohorts. 10% cases showed a hypermutator phenotype, enriched in HGG-E. CDK4 amplifications were recurrent in GBM-RTK1 and GBM-CBM. Histology showed variable cytological and architectural features within novel subgroups. TYA HGG comprise novel subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine future treatment.
IMG-07. MOLECULAR PROCESSES GIVE RISE TO EMERGENCE OF RADIO-PHENOTYPES ON MRI SCANS OF PEDIATRIC LOW-GRADE GLIOMA
Authors: Anahita Fathi Kazerooni, Adam Kraya, Meen Chul Kim, Debanjan Haldar, Komal Rathi, Aria Mahtabfar, Ariana Familiar, Nastaran Khalili, Ammar Naqvi, Mateusz Koptyra, Sina Bagheri, Hannah Anderson, Jeffrey B Ware, Phillip B Storm, Arastoo Vossough, Adam C Resnick, Christos Davatzikos, Ali Nabavizadeh
Journal: Neuro-Oncology (2023)

Abstract There is mounting evidence that tumor microenvironmental pressure selects for somatic genetic alterations that contribute to the formation of distinct morphological characteristics, captured on radiology scans as radio-phenotypes. Such phenotypic variations are a source of heterogeneity in clinical manifestation of tumors of the same histology across the patients, and in part, their heterogeneous responses to therapies. Deeper understanding of the associations between genotype and radio-phenotype in pediatric low-grade glioma (pLGG), the most histologically diverse childhood brain tumor, may facilitate precision diagnostic and therapeutic approaches. Here, we categorize pLGGs into distinct and relatively homogeneous imaging subtypes based on radiomic features and further explore the associations of these imaging subtypes with genotype. From multiparametric MRI scans of 167 pLGGs from the Children’s Brain Tumor Network (CBTN), 881 radiomic features and clinical variables (tumor location, age, and gender) were extracted. After dimensionality reduction using principal component analysis (PCA), K-Means clustering was applied on 19 principal components to group the patients into three imaging subtypes. Using whole transcriptomic data from OpenTargets, differential expression and co-expression of network- and pathway-level and immune-related signaling were compared among these three imaging subtypes. Gene Set Enrichment Analysis (GSEA) revealed differentially higher expression of cell cycle regulatory, extracellular matrix (ECM) remodeling, and cell migratory pathways in imaging subtype1 than subtypes 2 and 3, and upregulation of ECM and immune-related pathways in subtypes 1 and 2 compared to subtype3. Based on Gene Sets Net Correlations Analysis (GSNCA), subtype1 exhibited differential co-regulation of TNF/TNFR1 signaling compared to subtype2, and differential co-regulation of RHOG GTPase and TGFB1pathways when compared against subtype3. Subtype2 showed differential co-regulation in NOTCH1 signaling and transcriptional regulatory pathways. Our proposed multi-disciplinary radiomic-genomic analysis approach elucidates the molecular and biological processes in the genotype of the tumors that are associated with emergence of distinct imaging subtypes in pLGG.
DIPG-36. H3K27M HISTONE MUTANT GLIOMAS ARE SENSITIVE TO METHIONINE LOSS AND MAT2A INHIBITION THROUGH A NOVEL FEEDBACK MECHANISM BETWEEN AMD1 AND METTL16
Authors: Akanksha Chilukuri, Matthew Halbert, Brian Golbourn, Srinidhi Varadharajan, Brian Krug, Nneka Mbah, Stephanie Casillo, Taylor Gatesman, Andrea Cruz, Michael Zapotocky, Baoli Hu, Gary Kohanbash, Kelsey Bertrand, Claudia Kleinman, Costas Lyssiotis, Nada Jabado, Ian Pollack, Stephen Mack, Sameer Agnihotri
Journal: Neuro-Oncology (2023)

Abstract Diffuse Midline gliomas (DMGs) are grade IV tumors by the World Health Organization. They are inoperable and resistant to chemo/radiotherapies resulting in a median survival of 8-11 months and a 5-year survival of &amp;lt;2%. DMG is an epigenetic disease characterized by mutations on histone H3.3 K27M resulting in global transcriptional reprogramming. This disease lacks appropriate models to predict disease biology and response to treatment. Therefore, we developed a novel syngeneic H3K27M mouse model using clinically relevant co-alterations in Olig2+ neural progenitor cells (NPCs). Using an unbiased systems biology approach, we identified a reliance of H3K27M but not isogenic controls to the amino acid methionine, and the enzymes methionine adenosyltransferase 2A (MAT2A), and adenosylmethionine decarboxylase 1 (AMD1). MAT2A is a master regulator of methionine metabolism that converts methionine into the universal methyl donor S-adenosylmethionine (SAM) which is later converted into decarboxylated SAM (dcSAM) by AMD1 for polyamine metabolism. We postulated that targeting methionine regulator MAT2A through genetic/pharmacological abrogation would selectively alter DMG viability by disrupting the methylome. We discovered a novel mechanism demonstrating H3K27M cells are sensitive to MAT2A loss independent of methylthioadenosine phosphorylase (MTAP) deletions but rather through AMD1 overexpression. The current paradigm shows that MAT2A protein expression is inversely correlated with cellular SAM concentrations as sensed by splicing complex and m6A reader methyltransferase-like protein 16 (METTL16). To investigate the molecular mechanism by which H3K27M represses MAT2A, we postulated that dcSAM, the resultant metabolite of AMD1, promote(s) high turnover of METTL16–MAT2A transcript interactions like SAM, thereby diminishing MAT2A transcript and protein expression. We found that exogenous dcSAM promoted MAT2A intron retention and lower mature transcript levels. Our findings demonstrate that H3K27M leads to increased AMD1 protein expression resulting in diminished MAT2A expression. Combinatorial treatments inhibiting MAT2A and AMD1 may presents exploitable therapeutic vulnerabilities in these gliomas.
HGG-23. DECIPHERING THE RELATIONSHIP OF MICROSATELLITE-INSTABILITY AND MUTATIONAL BURDEN IN HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONALLY IMPAIRED DNA DAMAGE RESPONSE
Authors: Mirjam Blattner-Johnson, Dominik Sturm, Barbara C Jones, Christopher Previti, Philipp Sievers, Natalie Jäger, Steffen Hirsch, Nicola Dikow, Felix Sahm, Christof M Kramm, Olaf Witt, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2023)

Abstract Multiple large-scale genomic studies across pediatric tumors have reported an overall frequency of ~6-10% of patients with constitutional pathogenic variants, but associations of cancer predisposition with distinct tumor types vary between zero and 100%. We analyzed sequencing and DNA methylation data from 363 patients to explore the landscape of cancer predisposition in pediatric high-grade gliomas (pedHGG). Almost all pedHGG with constitutional alterations resulting in DNA mismatch repair deficiency (MMRD) were classified to IDH-mutant or pedRTK1a DNA methylation classes. Conversely, 70% of pedRTK1a and nearly 60% of IDH-mutant pedHGG (&amp;lt;18 years) arose in patients with either Lynch or cMMRD syndromes. Biallelic MMR inactivation (cMMRD) was found almost exclusively to affect the exchangeable part of the mismatch repair machinery complex (MSH6/PMS2; 75%), while heterozygous loss affected non-exchangeable core members MLH1 or MSH2 (93%). IDH-mutant MMRD tumors showed substantially lower overall tumor mutational burden (TMB &amp;lt; 40), less microsatellite instability, and frequent MSH6 mutation (60%), while pedRTK1-MMRD tumors often harbored additional alterations in POLE, leading to an ultra-mutator phenotype (TMB &amp;lt; 100), had higher microsatellite instability burden, and more often linked to PMS2 or MSH2 loss. Both IDH-mutant- and pedRTK1-MMRD tumors were associated with poor outcome, with MMRD-associated IDH-mutant pedHGG resulting in significantly shorter survival compared with sporadic IDH-mutant tumors (p=0.0015). We observed a nonlinear correlation between increasing numbers of point mutations, InDels and microsatellite instability. Exemplary, patients with pathogenic constitutional variants in MSH6 showed a significantly lower number of InDels compared with overall TMB, which might be due to repair ability of the replacement protein MSH3. As newer studies point towards an important role of InDels in antigen presentation and therefore as a potential biomarker for immune checkpoint inhibition, further exploration of these detailed molecular associations in conjunction with clinical outcome and response data is warranted.
XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY
Authors: Faye Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie Serkova, Nicholas Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan Dahl
Journal: Neuro-Oncology (2023)

Abstract Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
Versatile Detection of Diverse Selective Sweeps with Flex-Sweep
Authors: M Elise Lauterbur, Kasper Munch, David Enard
Journal: Molecular Biology and Evolution (2023)

Understanding the impacts of selection pressures influencing modern-day genomic diversity is a major goal of evolutionary genomics. In particular, the contribution of selective sweeps to adaptation remains an open question, with persistent statistical limitations on the power and specificity of sweep detection methods. Sweeps with subtle genomic signals have been particularly challenging to detect. Although many existing methods powerfully detect specific types of sweeps and/or those with strong signals, their power comes at the expense of versatility. We present Flex-sweep, a machine learning-based tool designed to detect sweeps with a variety of subtle signals, including those thousands of generations old. It is especially valuable for nonmodel organisms, for which we have neither expectations about the overall characteristics of sweeps nor outgroups with population-level sequencing to otherwise facilitate detecting very old sweeps. We show that Flex-sweep has the power to detect sweeps with subtle signals, even in the face of demographic model misspecification, recombination rate heterogeneity, and background selection. Flex-sweep detects sweeps up to 0.125*4Ne generations old, including those that are weak, soft, and/or incomplete; it can also detect strong, complete sweeps up to 0.25*4Ne generations old. We apply Flex-sweep to the 1000 Genomes Yoruba data set and, in addition to recovering previously identified sweeps, show that sweeps disproportionately occur within genic regions and are close to regulatory regions. In addition, we show that virus-interacting proteins (VIPs) are strongly enriched for selective sweeps, recapitulating previous results that demonstrate the importance of viruses as a driver of adaptive evolution in humans.
ATRT-05. DNA DAMAGE REPAIR INHIBITOR LP-184 INHIBITS CELL GROWTH IN ATRT
Authors: Hyuk Jean Kwon, Nisha Shah, Istabraq Musa, Eric Raabe
Journal: Neuro-Oncology (2023)

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric brain tumor. It is characterized by inactivation of SMARCB1 gene. There is currently no standard of care for treatment. LP-184 is an analog of acylfulvene. LP-184 induces cell-cycle arrest and cell apoptosis through alkylation of DNA and RNA. Previously, LP-184 was shown to have preclinical efficacy in temozolomide-resistant human glioblastoma cell lines. Additionally, it was reported that loss of SMARB1 increases sensitivity to LP-184. Therefore, we hypothesized that LP-184 may be effective against ATRTs. We have evaluated the effect of LP-184 in multiple ATRT cell lines, including CHLA06, CHLA266, and BT37. Treatment with LP-184 showed that LP-184 inhibits cell growth from 10nM to 200nM concentrations in an ATRT cell line (CellTiter Blue assay for BT37 p&amp;lt;0.0001 by t-test). We have identified an IC50 of 23.92nM. LP-184 induced apoptosis 96 hours after treatment in several ATRT cell lines as demonstrated by immunofluorescence for cleaved caspase-3 (CHLA06 p=0.0003 50nM vs DMSO, CHLA266 p=0.002 50nM vs DMSO, BT37 p=0.0014 50nM vs DMSO by t-test) and Western blot for c-PARP. LP-184 decreased proliferation 96 hours after treatment in several ATRT cell lines as demonstrated by immunofluorescence for Bromodeoxyuridine (BrdU) and Western blot for p-RB. Further evaluations of LP-184 treatment in vitro and in vivo are underway. Our in vitro data so far suggests that LP-184 is an effective potential therapeutic option for ATRT.
HGG-27. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASK FORCE
Authors: Logine Negm, Liana Nobre, Julie Bennett, Jiil Chung, Martin Komosa, Nick Fernandez, Michelle Ku, Monique Johnson, Vanessa Bianchi, Melyssa Aronson, Cindy Zhang, Lucie Stengs, Mary Jane Lim-Fat, Julia Keith, Derek Tsang, Andrew Gao, David G Munoz, Lananh Nguyen, Sunit Das, Adrian Levine, Anirban Das, Adam Resnick, David Wheeler, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond to immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) or Constitutional Mismatch Repair Deficiency (CMMRD). However, the prevalence of MMRD in gliomas of children, adolescents, and young adults (CAYA), and impact of germline inheritance is unknown. We utilized functional genomic tools on population-based and validation cohorts from 3 large databases (Toronto, St-Jude and CBTN) to determine the prevalence, subgroup, and impact of germline mutations on MMRD-gliomas. Ongoing data on 998 pediatric-gliomas from Toronto reveals that MMRD is extremely rare in pediatric low-grade gliomas (PLGG) but common in pediatric high-grade gliomas (PHGG) (9%, p&amp;lt;0.0001). Similarly, data from St-Jude and CBTN (n=374) reveals that MMRD exists only in PHGG (8%). In both cohorts, MMRD-PHGG are enriched for RAS/MAPK, IDH, and TP53 mutations while pediatric-type fusions, BRAF-V600E and histone mutations are absent. In AYA-HGG (n=884), the most common groups include glioblastomas without chromosome-7/10 alterations (9%) and IDH1-astrocytomas, while MMRD is not present in IDH-oligodendrogliomas. All but 1 CAYA-MMRD-gliomas harbored germline MMR mutations. Data from the IRRDC on 174 patients reveal that LS is more common than CMMRD in gliomas, with the median age of onset 11 and 29 years in CMMRD and LS, respectively (p&amp;lt;0.001). Furthermore, CMMRD gliomas are commonly caused by germline PMS2 and MSH6 mutations, enriched for secondary polymerase mutations (60%, p&amp;lt;0.001), and exhibit ultra-hypermutation. In contrast, LS-gliomas are caused by MSH2 and MLH1 mutations, and enriched for IDH1 mutations (32%, p&amp;lt;0.025) with a lower mutational burden. Our data reveals high prevalence of MMRD in CAYA-HGG with alarming impact of germline predisposition. Specifically, unrecognized LS patients with AYA MMRD-HGG. These findings support universal screening for MMRD in HGG to identify patients for immunotherapy and surveillance.
DIPG-57. TESTING FOR SYNERGY AMONG RADIATION AND HIGHLY CLINICALLY RELEVANT CHEMOTHERAPEUTIC AGENTS IN PATIENT-DERIVED MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Mathew Slade, Gabrielle Link, John DeSisto, Charlotte Feddersen, Damien Bargas, Aaron Knox, Adam Green
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors with minimal long-term survival. Radiation is currently the only standard-of-care treatment and is non-curative. Several chemotherapy agents have shown preclinical and/or early clinical promise, and we hypothesize that finding effective chemoradiotherapeutic combinations is likely to be necessary to achieve long-term survival, based on experience from other previously incurable childhood cancers. We treated 8 DMG/DIPG cell lines with one, two, or three treatments among the HDAC inhibitor panobinostat, the CDK4/6 inhibitor ribociclib, the DRD2 inhibitor ONC201, the XPO1 inhibitor selinexor, the PI3K inhibitor paxalisib, and radiation. We then measured the cell survival with MTS assays. Cells were treated with drug concentrations ranging from 1 nM to 100 uM. To assess for synergy among our combinations, we used the Combination Index (CI) model, in which a score of &amp;lt;1 implies synergy. Of the 15 2-treatment combinations, ONC201 + radiation, ONC201 + paxalisib, ribociclib + ONC201, selinexor + paxalisib, and ribociclib + paxalisib met our criteria as successful, synergistic combinations: at least three cell lines with at least 90% cell death achieved, a CI value of 0.5 or lower at doses with at least 50% cell death, and at least 66% of dose levels with a CI value of 0.5 or lower. Early analysis suggests that ribociclib + ONC201 + paxalisib, ONC201 + paxalisib + radiation, and ONC201 + selinexor + paxalisib are the most effective three-treatment combinations. Patient-derived cell culture data in a heterogeneous pool of DMG/DIPG cell lines demonstrate synergy using several combinations of clinically relevant treatments, especially those including paxalisib. We are now optimizing treatment sequencing in synergistic combinations and testing in orthotopic xenograft models. Our goal is to find combinations that can become cycles of therapy in a multimodality clinical trial.